”When something like that happens within a family, the cause is typically a genetic mutation. Genetic testing for mutations in genes known to be involved in sudden cardiac death was performed on blood samples from members of the Swedish family over the course of several years without identifying any cause of the disease. It was not until the development of new genetic technologies, enabling examination of the entire genome at once, that things started progressing. At this point, Mette Nyegaard, Associate Professor in Humane Genetics at Aarhus University, took over the project, and with the samples available she reached the conclusion that there were two regions in the genome where the mutation could be located.”
Analysis of two new blood samples from children in the family became the key to resolving this: They were different in the two suspected genomic regions, and one of the children had recently fainted. This allowed identification of the genomic region harbouring the disease-causing mutation.
The researchers now needed to identify which of the 70 genes in that specific part of the genome was the cause of the arrhythmia, and this is where Michael Toft Overgaard was brought in due to his expertise in proteins.
- ”We managed to identify the mutation and the protein that was affected: The calmodulin protein which senses and controls the calcium levels in all human cells. The calcium level in cells is crucial for a vast number of bodily functions, including muscle contractions – and thus the beating of the heart. It is in fact so essential to control calcium that when we first started communicating our results, many researchers had a hard time believing us. The importance of calmodulin is so high that it is one of the most static proteins in the history of evolution – the protein is identical in all vertebrates – and the human genome even has three copies of the gene producing exactly the same protein. Up until our discovery, no one thought it was possible to actually live with a mutation in a calmodulin-encoding gene” Michael Toft Overgaard says.
The researchers’ discovery has meant a significant improvement for the Swedish family:
Previously, all members of the family were constantly on medication that dulled their adrenaline responses, as this is what triggers the arrhythmia. Now, everyone, including new-borns, can be tested and get a clear answer to whether they carry the mutation – and is at risk – and those who carry it can either get medicated or get a small ICD, an advanced pacemaker, implanted
Searching for further insights – and a treatment
The researchers’ work does not end here, though: Now, the search has begun for an understanding of the disease mechanism and a possible treatment.
- “Our research group now continues the research into the functions and interactions of calmodulin. In the summer of 2015, I received a grant from the Danish Council for Independent Research for the continued studies of the protein, specifically the differences between normal and mutated variants and the way calmodulin interacts with calcium ions in the body, and we now have three PhD students and one Postdoctoral fellow participating in the work,” Michael Toft Overgaard says.
It is important to reach an understanding of why a mutation in the protein only affects one function in the body and not all the functions in which calmodulin plays a crucial role – and the mechanism for how the mutations cause these fatal malfunctions. If we understand why proteins and processes malfunction, we are also closer to knowing what to do to alleviate these malfunctions
In addition to this work, Michael Toft Overgaard and Mette Nyegaard now collaborate on finding a cure for the unfortunate who carry the mutation:
- “Our results show that the mutated calmodulin protein primarily affects the calcium channel that regulates the outflow of calcium from stores within the cells of the heart, causing that calcium flow to malfunction. We can use this new insight to search for a medicine that influences the way calmodulin works in that exact context. Mette Nyegaard and I have received funding from CapNova and the Proof of Concept programme under the Danish Agency for Science, Technology and Innovation for continuing this work through the spinoff company CamAgon” Michael Toft Overgaard says.
The company rents lab facilities at Aalborg University’s Department of Chemistry and Bioscience – including a brand new, state-of-the-art robot pipetting system, obtained through a generous grant given to AAU by the Obel Family Foundation – ensuring a close interaction between the company’s research and the continued protein research that Michael Toft Overgaard and his research group perform.
- “If we can reach a deeper understanding of the disease mechanism and find a solution – for instance a way of controlling how large the calcium flow within the cells is – this has a huge potential. Calcium is connected to a great number of other disorders, including heart insufficiency, so if we can solve this one, we may have a solution for a range of others too” Michael Toft Overgaard finishes.